scholarly journals Genomic Action of Sigma-1 Receptor Chaperone Relates to Neuropathic Pain

2021 ◽  
Author(s):  
Shao-Ming Wang ◽  
Nino Goguadze ◽  
Yuriko Kimura ◽  
Yuko Yasui ◽  
Bin Pan ◽  
...  
Keyword(s):  
Neuropathic Pain ◽  
Action Potentials ◽  
Neuronal Excitability ◽  
Mrna Translation ◽  
Sigma 1 Receptor ◽  
Voltage Gated ◽  
Sigma 1 ◽  
Frequency Of Action Potentials ◽  
Translational Inhibitor ◽  
Ca2 Channels

AbstractSigma-1 receptors (Sig-1Rs) are endoplasmic reticulum (ER) chaperones implicated in neuropathic pain. Here we examine if the Sig-1R may relate to neuropathic pain at the level of dorsal root ganglia (DRG). We focus on the neuronal excitability of DRG in a “spare nerve injury” (SNI) model of neuropathic pain in rats and find that Sig-1Rs likely contribute to the genesis of DRG neuronal excitability by decreasing the protein level of voltage-gated Cav2.2 as a translational inhibitor of mRNA. Specifically, during SNI, Sig-1Rs translocate from ER to the nuclear envelope via a trafficking protein Sec61β. At the nucleus, the Sig-1R interacts with cFos and binds to the promoter of 4E-BP1, leading to an upregulation of 4E-BP1 that binds and prevents eIF4E from initiating the mRNA translation for Cav2.2. Interestingly, in Sig-1R knockout HEK cells, Cav2.2 is upregulated. In accordance with those findings, we find that intra-DRG injection of Sig-1R agonist (+)pentazocine increases frequency of action potentials via regulation of voltage-gated Ca2+ channels. Conversely, intra-DRG injection of Sig-1R antagonist BD1047 attenuates neuropathic pain. Hence, we discover that the Sig-1R chaperone causes neuropathic pain indirectly as a translational inhibitor.

Deoxyglucose and reduced glutathione mimic effects of hypoxia on K+ and Ca2+ conductances in pulmonary artery cells

1994 ◽  
Vol 267 (1) ◽  
pp. L52-L63 ◽  
Author(s):  
X. J. Yuan ◽  
M. L. Tod ◽  
L. J. Rubin ◽  
M. P. Blaustein
Keyword(s):  
Pulmonary Artery ◽  
Action Potentials ◽  
Reduced Glutathione ◽  
Metabolic Inhibitors ◽  
Common Mechanism ◽  
Pipette Solution ◽  
Voltage Gated ◽  
Kv Channels ◽  
Channel Inhibition ◽  
Ca2 Channels

Hypoxia-induced pulmonary vasoconstriction (HPV) is triggered by a rise in cytosolic Ca2+ concentration ([Ca2+]i) that is partially controlled by voltage-gated Ca2+ channels. Hypoxia inhibits voltage-gated K+ (KV) channels in pulmonary artery (PA) myocytes. This depolarizes the cells, opens voltage-gated Ca2+ channels, thereby increases [Ca2+]i, and initiates HPV. In intact animals and isolated perfused lungs, metabolic inhibitors and reducing agents augment HPV. We compared the effects of hypoxia with the glycolysis inhibitor, 2-deoxy-D-glucose (2-DOG), and the reducing agent, reduced glutathione (GSH), on voltage-gated steady-state K+ currents (IK,ss) and membrane potential (Em) in cultured rat pulmonary and mesenteric arterial (MA) smooth muscle cells. Bath application of 10 mM 2-DOG (glucose-free) or 5-10 mM GSH reversibly reduced IK,ss by 25-35% in PA myocytes, with 5 mM ATP present in the pipette solution. Neither hypoxia nor 2-DOG significantly affected IK,ss in MA myocytes, but GSH did reduce IK,ss in these cells. Furthermore, hypoxia, 2-DOG, and GSH depolarized PA cells in the absence as well as in the presence of external Ca2+. Hypoxia, 2-DOG, and GSH also evoked action potentials on the top of the steady depolarization in 36-50% of PA myocytes but not in any MA myocytes; removal of external Ca2+ abolished the action potentials without affecting the steady depolarization. These effects were comparable to those produced by 4-aminopyridine (5-10 mM), a blocker of KV channels. This implies that the action potentials are attributable to Ca2+ influx through voltage-gated Ca2+ channels opened by the steady depolarization due to KV channel inhibition. In the presence of 2-DOG or GSH, hypoxia had no further effect on IK,ss or Em in PA cells; this implies that hypoxia, 2-DOG, and GSH all block the same K+ channels. The data suggest that 1) the hypoxia-induced decrease of IK,ss and the resultant depolarization in PA myocytes may be related to a local decrease of intracellular ATP level and/or a change in redox status of the membrane or cytosol and 2) extracellular Ca(2+)-dependent action potentials may be responsible for at least part of the increase in [Ca2+]i during HPV. Similarities between the effects of hypoxia, 2-DOG, and GSH on IK,ss and Em in PA myocytes, along with the dissimilar responses of PA and MA myocytes, suggest that a common mechanism may underlie the responses of PA cells to these treatments.

Possible involvement of the sigma-1 receptor chaperone in chemotherapeutic-induced neuropathic pain

Synapse ◽  
2015 ◽  
Vol 69 (11) ◽  
pp. 526-532 ◽  
Author(s):  
Mori Tomohisa ◽  
Ohya Junpei ◽  
Masumoto Aki ◽  
Harumiya Masato ◽  
Fukase Mika ◽  
...  
Keyword(s):  
Neuropathic Pain ◽  
Sigma 1 Receptor ◽  
Sigma 1

Sigma‐1 receptor antagonist ( BD ‐1063) potentiates the antinociceptive effect of quercetin in neuropathic pain induced by chronic constriction injury

2020 ◽  
Author(s):  
Josué Vidal Espinosa‐Juárez ◽  
Osmar Antonio Jaramillo‐Morales ◽  
Myrna Déciga‐Campos ◽  
Luis Alfonso Moreno‐Rocha ◽  
Francisco Javier López‐Muñoz
Keyword(s):  
Neuropathic Pain ◽  
Receptor Antagonist ◽  
Chronic Constriction Injury ◽  
Antinociceptive Effect ◽  
Sigma 1 Receptor ◽  
Sigma 1

216 A NEW SELECTIVE SIGMA-1 RECEPTOR ANTAGONIST (S1RA) REDUCES NEUROPATHIC PAIN BEHAVIORS AND ACTIVITY-INDUCED SPINAL SENSITISATION

2010 ◽  
Vol 4 (S1) ◽  
pp. 63-63 ◽  
Author(s):  
D. Zamanillo ◽  
L. Romero ◽  
J. Burgueño ◽  
X. Nadal ◽  
A. Dordal ◽  
...  
Keyword(s):  
Neuropathic Pain ◽  
Receptor Antagonist ◽  
Sigma 1 Receptor ◽  
Pain Behaviors ◽  
Sigma 1
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